Alterations in chemically-induced liver injury by immunomodulators

Abstract

Studies presented in this dissertation determined biochemical mechanisms underlying the modulation of chemical-induced liver injury by retinol and GdC₃ The first objective was to determine the role of inflammatory cells in the retinol potentiation of CCl₄-induced liver injury. Plasma alanine aminotranferase activities and histological analysis of liver sections both illustrated significant potentiation of CCl₄ hepatotoxicity by a single dose of retinol. The mechanism for this potentiation involves priming of Kupffer cells (KC) (i.e. by enhancing their response to toxic stimuli) as established by chemical inhibitors of KC, isolated KC, and immunohistochemical analysis of liver sections. Additional studies estimated the effect of retinol on non-inflammatory processes (i.e. cytochrome P450 (P450) activity). While total P450 content was not increased, the activity and concentration of CYP 2E1 were both significantly elevated following treatment with a single dose of retinol. These findings suggest that a single pretreatment with retinol potentiates CCl₄ hepatotoxicity by multiple mechanisms that involve increased biotransformation and inflammatory cell activities. Based on the findings with retinol, another immunomodulating agent, GdCl₃ might also alter the activity of hepatic biotransforming enzymes. Having established that GdCl₃ inhibits the activity of KC, the purpose of these studies was to determine the effect of GdCl₃ on the content and activity of hepatic P450. GdCl₃ treatment reduced total hepatic microsomal P450 as well as aniline hydroxylase activity by 30% in male and 20% in female rats. Hepatocytes isolated from rats pretreated with GdCl₃ were less susceptible to toxicity caused by CCl₄ but not cadmium, a hepatotoxic chemical not bioactivated by P450. Thus GdCl₃-mediated protection from toxicity in vivo might involve decreased biotransformation and inflammatory cell activities. Data presented in this dissertation suggest that, in addition to altering the inflammatory response to toxicants, retinol and GdCl₃ may modulate liver injury by altering the P450-mediated bioactivation of chemicals. Considering the multiple effects described here for each of these compounds, investigators should be cautious in the interpretation of data utilizing retinol or GdCl₃ to implicate KC as the sole contributor to toxicological mechanisms. This is especially important in models of chemical-induced injury in which bioactivation is a key feature.